Mantle cell lymphoma (MCL) is a well-defined subtype of B cell lymphoma in the World Health Organization classification, and accounts for approximately 3-10% of all non-Hodgkin lymphomas. The chromosomal aberration t(11;14)(q13;q32) can be found in practically all cases of MCL. The translocation results in juxtaposition of the immunoglobulin heavy chain joining region on chromosome 14 to the cyclin D1 gene on chromosome 11. The molecular consequence of the translocation is to place cyclin D1 under the control of the immunoglobulin heavy chain gene enhancer, leading to over-expression of the cyclin D1 protein.
Although MCL accounts for approximately 3-8% of B-cell lymphomas, it is difficult to manage. Initial treatment with rituximab plus combination chemotherapy or purine analogues results in complete remission (CR) rates varying from 34-87%. However, relapses occur in most patients with prolonged follow up. Treatment options for relapsed patients are limited. Several approaches have been adopted, including the use of the proteasome inhibitor bortezomib, thalidomide and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus. The overall response (OR) rates of these agents varied from 38-81%, but the CR rate was only 3-31%. Therefore, there is an urgent need to define effective treatment strategies for MCL.
It is an object of this invention to provide agents and methods for treating cancers such as MCL and other cancers over-expressing cyclin D1.
It is another object of this invention to provide methods, strategies, doses, and dosing schedules for the administration of As2O3 in the clinical inhibition of cancers over-expressing cyclin D1.